Abstract
The HIV-1 envelope (Env) mediates viral entry into host cells. While static images of Env define distinct conformations, direct observations of Env dynamics have yet to be realized. To enable real-time imaging of conformational events in Env, we introduced fluorophores into the variable regions of the Env gp120 subunit and measured single-molecule fluorescence resonance energy transfer (smFRET) within the context of native trimers on the surface of HIV-1 virions. We observed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between 3 distinct pre-fusion conformations, and receptor CD4 and co-receptor surrogate antibody 17b to remodel the conformational landscape of Env. Differences in conformational dynamics and ligand responsiveness of neutralization-sensitive and neutralization-resistant HIV-1 isolates delineated the dynamics-based mechanism of immune evasion. smFRET also revealed neutralizing antibodies VRC01, PG16, PGT128, PGT145, and 2G12, and the entry inhibitor, BMS-626529, to stabilize the ground state of Env, thereby providing dynamics-based strategies for therapeutic intervention.
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